A controlled release profile from a drug dosage form is sometimes desirable in clinical use to reduce side effects and improve patient compliance. The technology used to formulate sustained release dosage forms is well documented. The entrapment of a drug in a polymer based matrix is a common approach to formulate sustained release tablets with a desirable release profiles.
It has been reported that depot drug formulations for controlled release of pharmaceutical drugs may be prepared using alginates alone (see U.S. Pat. No. 5,132,295), using combinations of alginates and polyacrylates (see U.S. Pat. No. 5,230,901) and using combinations of alginates and a pH independent gelling agent, such as, for example, hydroxypropyl methylcellulose (see U.S. Pat. No. 4,792,452). It is also known that the use of alginates alone for this purpose often presents difficulties in tableting, film coating and storage.
It also has been reported that a sustained release dosage form useful in providing once-a-day medication consists of the admixture of hydroxypropyl methylcellulose (viscosity of 80 to 120 cps in a 2% aqueous solution) and ethylcelluose with etodolac (see U.S. Pat. No. 4,966,768). Using a low viscosity of hydroxypropyl methylcellulose with ethylcellulose as rate controlling agents in the formulation may give a shorter T.sub.max (time to peak blood concentration) after oral administration due to a fast tablet erosion.
Adding polyacrylates to the alginate formulation overcomes these difficulties to some extent; however, tablets formed using alginates and polyacrylates often have a pH dependent dissolution profile. In a low pH environment, alginates and polyacrylates do not swell and/or dissolve properly. This leads to drug release by a diffusion mechanism through non-viscous capillaries resulting in a different dissolution rate than in a high pH environment. On the other hand, in a high pH environment, alginates swell and become soluble while polyacrylates may or may not do the same. This leads to drug release both by erosion and diffusion at a rate which is different than the low pH release rate.
In formulations which contain an alginate and a pH independent gelling polymer such as, for example, hydroxypropyl methylcellulose, hydration at low pH levels forming a viscous gel layer for drug release. At high pH levels, however, tablets become smaller and smaller during drug release due to erosion of the swollen polymer layer, leading to a reduction in surface area which may affect the dissolution rate of a tablet.
The novelty of the present invention is the provision of a sustained release formulation which reduces, and perhaps eliminates the aforementioned problems completely. In particular the invention provides a controlled release drug formulation which includes novel formulations containing three different types of polymers. These three different types of polymers include: 1) a water insoluble polymer, such as ethylcellulose; 2) a pH independent gelling polymer, such as hydroxypropyl methylcellulose; and 3) a pH dependent gelling polymer, such as sodium alginate. These three different types of polymers must be used together to achieve a controlled release rate of the selected drug. Such a combination of polymers facilitates manufacturing processes and improves drug release and absorption profiles.
In accordance with the present invention, the combination of the three polymers provides an excellent matrix drug depot system with desirable controlled release characteristics. During dissolution at low pH levels, such as in the stomach, the pH independent gelling polymer e.g., hydroxypropyl methylcellulose, hydrates and swells to form a hydrogel which controls drug release from the matrix system. Drug release may be due to the gel layer erosion or drug diffusion through the gel layer or a combination of both. The water insoluble polymer e.g., ethylcellulose, and the pH dependent gelling polymer e.g., sodium alginate, are dispersed in the gel layer as insoluble parties to block the diffusion pathway or adjust the erosion rate of the gel layer. All the three polymers play important roles to control drug release at a low pH environment. As the matrix system moves to a higher pH environment e.g. in the intestinal tract, the tablet surface area becomes smaller due to the gel layer erosion, which may lead to a reduction of drug release rate. However, the pH dependent gelling polymer dispersed in the gel layer starts to hydrate and swell. Meanwhile, the insoluble particles dispersed in the gel layer will be reduced due to the hydration of pH dependent gelling polymer, resulting of the opening of additional diffusion channels. Therefore, hydration of the pH dependent polymer and concomitant reduction of the insoluble particles in the hydrogel in high pH environment, will compensate the reduction tendency of the drug release rate due to the surface area changes resulting from erosion. Thus, drug release rate is maintained regardless of the pH and tablet size changes. Thus, the formulations of the present invention provide improved drug release profiles compared with the prior art formulations described above.